PROJECT SUMMARY The North Texas Hepatitis B Consortium (NTHBC) comprises two medical institutions, and three distinct practice locations in the Dallas Fort Worth metroplex. NTHBC has participated fully in the first 7-year grant cycle, with the third highest enrollment among the 13 participating sites, good retention and ongoing participation in the Immune Active and Immune Tolerant clinical therapy trials. Drs. Perrillo and Lee have served on a variety of committees and proposed a number of ancillary studies, some of which are already under way. One of the goals of HBRN is to better define the varied immunologic presentations of chronic infection. Along these lines, the NTHBC proposes an ancillary study of a currently poorly explored sub-phenotype, that of concurrent hepatitis B surface antigen and anti-HBs. Herein, we review what is currently known about this anomalous group of patients, and seek to compare this group with others such as patients in a parallel network, the Acute Liver Failure Study Group, that is overseen by Dr. Lee. Prior studies in hepatitis B related acute liver failure (HBVALF) suggest that more than 50% of ALF patients are concurrently HBsAg and anti-HBs positive. Data from HBRN suggest that at least 6% of chronic hepatitis B subjects display this dual serologic status but appear to lack very active liver disease. One explanation might be that concurrent positivity results from infection with different subtypes but this is not substantiated by data suggesting common epitopes across all HBsAg genotypes and serotypes. The current study aims to explore the phenotype further, correlating it with clinical disease features, length of infection and time to subsequent HBsAg clearance and disease evolution over time. Understanding this phenotype better will lay the groundwork for molecular sequencing studies to better understand the mutation profile of the concurrently positive patients as compared to those with HBV ALF (typically more frequent mutations) and those with chronic hepatitis B without concurrence. These analyses are likely to offer new and important insights into HBV-specific immunological paralysis that leads to chronic infection, yielding new strategies for viral clearance.